title: Reciprocal regulation of hepatic and adipose lipogenesis by liver X receptors in obesity and insulin resistance.
abstract: Liver X receptors (LXRs) regulate lipogenesis and inflammation, but their contribution to the metabolic syndrome is unclear. We show that LXRs modulate key aspects of the metabolic syndrome in mice. LXRαβ-deficient-ob/ob (LOKO) mice remain obese but show reduced hepatic steatosis and improved insulin sensitivity compared to ob/ob mice. Impaired hepatic lipogenesis in LOKO mice is accompanied by reciprocal increases in adipose lipid storage, reflecting tissue-selective effects on the SREBP, PPARγ, and ChREBP lipogenic pathways. LXRs are essential for obesity-driven SREBP-1c and ChREBP activity in liver, but not fat. Furthermore, loss of LXRs in obesity promotes adipose PPARγ and ChREBP-β activity, leading to improved insulin sensitivity. LOKO mice also exhibit defects in β cell mass and proliferation despite improved insulin sensitivity. Our data suggest that sterol sensing by LXRs in obesity is critically linked with lipid and glucose homeostasis and provide insight into the complex relationships between LXR and insulin signaling.
authors.affiliation: Howard Hughes Medical Institute and Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
authors.forename: Simon W
authors.initials: SW
authors.lastname: Beaven
authors.forename: Aleksey
authors.initials: A
authors.lastname: Matveyenko
authors.forename: Kevin
authors.initials: K
authors.lastname: Wroblewski
authors.forename: Lily
authors.initials: L
authors.lastname: Chao
authors.forename: Damien
authors.initials: D
authors.lastname: Wilpitz
authors.forename: Tu Wen
authors.initials: TW
authors.lastname: Hsu
authors.forename: Jacob
authors.initials: J
authors.lastname: Lentz
authors.forename: Brian
authors.initials: B
authors.lastname: Drew
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Hevener
authors.forename: Peter
authors.initials: P
authors.lastname: Tontonoz
mesh_terms: D000273:Adipose Tissue / Q000502:physiology*; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000503:physiopathology; D015309:Glucose Clamp Technique; D006706:Homeostasis / Q000502:physiology; D007333:Insulin Resistance / Q000502:physiology*; D050155:Lipogenesis / Q000502:physiology*; D008099:Liver / Q000502:physiology*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000502:physiology; D009765:Obesity / Q000503:physiopathology*; D057093:Orphan Nuclear Receptors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D047495:PPAR gamma / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D051779:Sterol Regulatory Element Binding Proteins / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D000071518:Liver X Receptors; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D051779:Sterol Regulatory Element Binding Proteins; D014157:Transcription Factors